Rachael Song

The critical need for COVID-19 therapeutics has helped to underscore an ongoing urgent need for more innovative clinical designs.

According to Operation Warp Speed’s Janet Woodcock, the COVID-19 pandemic has put a spotlight on long-standing inefficiencies in the U.S. clinical trials enterprise.

 Early in the pandemic, Woodcock, then director of the U.S. Food and Drug Administration’s (FDA) Center for Drug Evaluation and Research (CDER), warned that clinical trial apparatus could be overwhelmed if master protocols, other platform approaches and adaptive designs were not adopted to more efficiently study potential COVID-19 treatments and vaccines.

Master protocols, especially platform trials, have recently garnered attention in COVID-19 studies. One example we’ve been supporting is NIH’s 

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)

 program, a public-private partnership to develop a coordinated research strategy for speeding development of the most promising treatments and vaccine candidates. ACTIV-2 is a master protocol designed for evaluating multiple investigational agents compared to placebo in adults with mild-to-moderate COVID-19.

However, across the broader R&D pipeline, master protocols continue to be underutilized.

This is a missed opportunity. In 2018, FDA drafted guidance, 

Master Protocols: Efficient Clinical Trial Design Strategies to Expedite Development of Oncology Drugs

. The guidance reads: “In contrast to traditional trial designs, where a single drug is tested in a single disease population in one clinical trial, master protocols use a single infrastructure, trial design, and protocol to simultaneously evaluate multiple drugs and/or disease populations in multiple substudies, allowing for efficient and accelerated drug development.”

Depending on the statistical design, master protocols can offer significant benefits:

Increased speed and quality of decisions: Accelerating successful investigations and discontinuing failing interventions sooner

Reduced costs: Sharing trial infrastructure, design and protocol (e.g., cost efficiencies from shared site recruitment, investigational sites, administration, control arms, systems, overhead, etc.). Deloitte estimates master protocols reduce costs by an estimated 13-18%

Shortened timeline: Deloitte estimates master protocols reduce timelines by 12-15%

Streamlined regulatory submission, review and amendment processes: Efficiencies can be gained from a single master protocol submission and shared regulatory, Institutional Review Board (IRB)/Ethics Committee (EC) and review committees

Patient allocation: Patients can be screened and allocated to the most appropriate substudies with applicable treatments

Though the potential benefits are large, so, too, are the operational considerations. This is particularly true for umbrella and platform studies, which are often large, complex, resource-intensive, competitive and constantly evolving. These studies may involve multiple life sciences companies and investigative agents both as monotherapy and in combination. Operational activity is not sequential, but instead happens concurrently. For example, it is common for a platform study to have some substudies in startup mode, some actively enrolling and some closed out.

Studies that use master protocols are not “business as usual.” In our experience, these operational guidelines can help smooth the way.

1. Leadership presents a clear and consistent core goal/philosophy to guide decision-making.

 When embarking on a study that uses a master protocol, it’s important to articulate a clear vision and philosophy. This can become particularly critical when there are competing interests (e.g., the needs of different partners or different substudies). Every decision, in turn, must be grounded in your core goal/philosophy. For example, if patient centricity is identified as the core goal, you might pressure test proposed changes by asking: “How will this change help the patient?”

2. Regulatory engagement (early and often).

 Sponsors may worry about diverging from traditional regulatory pathways. Our experience is that regulatory agencies encourage master protocols and welcome dialogue with sponsors pursuing their use. Early engagement with regulatory agencies is critical. FDA, for example, strongly encourages sponsors to discuss plans to develop drugs under a master protocol with the clinical review division early in the program to obtain feedback. 

FDA also can serve as a valuable source to provide feedback on emerging issues. In one complex umbrella trial studying more than 10 investigational compounds, for example, the principal investigators (PIs) became overwhelmed by cross reports. A consultation with FDA minimized cross-reporting requirements by excluding expedited reporting for events that occurred as natural history of disease.

3. Upfront and ongoing planning in the face of near constant change.

 De-risking the complexity inherent in a master protocol structure—while operating in a state of constant change—demands rigorous planning. This effort may start with the development of an integrated quality and risk management plan (IQRMP) that defines answers about the who, what, where, when, why and how in relation to an evolving protocol. The IQRMP defines the actions each functional group and party will take to proactively identify, assess and manage risk throughout the life of the master protocol and substudies. Built with the understanding that it’s impossible to foresee all the risks at study initiation, an IQRMP should incorporate flexibility to adapt to the speed and frequency of the changes associated with master protocols. Rather than trying to predict a fixed future, the IQRMP serves as a tool to understand the data that will be available at each point to make real-time decisions as the study evolves.

Given the inevitability of a constantly changing environment, it’s also important to plan and budget for ongoing adjustments in study documents including the protocol, Informed Consent Form (ICF), contract, budget and clinical supplies. Effective communication and clear processes are also essential to guard against site and team fatigue. Planning out the smallest details, for example, accurately labelling lab kits to clearly differentiate which treatment arm/cohort they belong to, can go a long way to reduce the risk of errors.

4. Flexible and scalable systems and technology capable of accommodating a master protocol. 

Using a shared infrastructure and study database across substudies can be an efficiency—and a challenge. Systems must be capable of both scaling across and adapting to the evolving—and differing—needs of the master protocol and substudies. At the same time, more frequent protocol changes demand frequent system and interface updates.

One of the primary key success factors for master protocol studies is the real-time collection and analysis of data with high quality to enable real-time decision making. This is extremely challenging in a fast-paced and constantly evolving study with complex protocol design.

Moreover, the pace of change can be exponential. In one umbrella study, for example, we expanded a six-cohort study into a 25-cohort study in response to signals seen as we expanded into Phase II. While this study ultimately accomplished under one umbrella what may have taken 10 to 15 traditionalstudies to achieve, it required eight substantial protocol amendments and 25 database modifications. Although these changes were strategically grouped to minimize site fatigue, they would have still strained most systems. Long-term programmatic solutions capable of analyzing enormous data sets—and an anticipation of incremental study expansion—built into systems from the onset can help accommodate the unique demands of master protocol trials.

Innovative technology tools also help smooth protocol amendment implementation by capturing and transferring key protocol data elements, streamlining data flow and speeding up protocol amendment process. Consider, for example:

A simulation tool that models different scenarios including the study endpoints, target population, sample size and power determination to help determine protocol design changes and drive the protocol amendment

A simulation tool that models different scenarios including the study endpoints, target population, sample size and power determination to help determine protocol design changes and drive the protocol amendment

A study planning tool that models the protocol change (e.g., adding or removing cohorts, change of sample size, interim analysis, eligibility criteria) and generates different study strategy scenarios to help facilitate cohort management and the implementation of downstream operational activities.

An orchestrated workflow with an integrated system infrastructure to help synchronize the changes in various systems, streamline the dataflow, and reduce the possibility of errors due to systems not being updated at the same time.

Interoperability between systems also should be assessed. Traditionally, the downstream work activities conducted by parties in a trial (e.g., regulatory affairs, ethics committees, IRBs, sponsors, CROs, vendors and sites) are carried out using different processes and systems. A lack of interoperability might be manageable in a single traditional study, but when multiplied by five, 10 or more substudies can threaten to overwhelm a trial. Technology innovations potentially can help break the cross-organizational barriers and create efficiency and synergy. Figure 1 portrays just one example.

Figure 1. Integrated communications platform across organizations in a basket trial

 Teams working on master protocols must be prepared to operate in an environment characterized by constant change. Using a master protocol, teams are given the flexibility to take 

 midstream to add or remove indication cohorts and drug combinations, while conducting other investigations in response to findings without having to go back to the drawing board to write a new protocol and set up additional studies.

, managing the magnitude of the cascade of activities that the addition and removal of substudies can cause. A team that balances master protocol and therapeutic experience with an open and adaptable mindset is an ideal mix.

Flexibility in vendors is equally important. Are the vendors willing to invest in making their processes more flexible? “Our SOP doesn’t allow that,” is not the response you want to hear from a vendor as you brainstorm solutions for emerging issues. Master protocol trials demand an open collaborative process in which participants bring their most innovative solutions to the table.

Regulatory authorities and forward-thinking clinical trial teams are increasingly embracing a range of advanced clinical trial designs—as we have seen particularly in COVID-19 and oncology studies. Unfortunately, adoption of master protocols across the broader R&D pipeline has been, at least in part, hampered by deeply entrenched habits and mindsets.

The key to adoption of master protocols is to keep an open mind while, at the same time, analyzing the complexity and potential benefits for your specific clinical trial. While the scientific and operational challenges of clinical trials that use master protocols are real, our experiences have shown again and again that the efficiencies and benefits far outweigh the complexities.

In fact, once you have experienced a master protocol’s innate adaptability, enhanced decision-making, and expedited development, you may find that a return to traditional methods might strike you as inflexible, inefficient, and slow.

, is Vice President, Oncology, Global Product Development;

Early Development, Hematology/Oncology Therapeutic Unit;

is Senior Director, Early Development, Hematology/Oncology Therapeutic Unit; and

COVID-19 Should Force ‘Soul Searching’ Over Fragmented US Clinical Trials System, Woodcock Says. 

. Published October 8, 2020. Accessed October 20, 2020. https://pink.pharmaintelligence.informa.com/PS143029/COVID19-Should-Force-Soul-Searching-Over-Fragmented-US-Clinical-Trials-System-Woodcock-Says

Woodcock Warns Research Apparatus Could Be Overwhelmed If Coronavirus Trials Don’t Use Master Protocols. 

. Published April 28, 2020. Accessed January 15, 2021. https://pink.pharmaintelligence.informa.com/PS142080/Woodcock-Warns-Research-Apparatus-Could-Be-Overwhelmed-If-Coronavirus-Trials-Dont-Use-Master-Protocols

Food and Drug Administration. Master protocols: efficient clinical trial design strategies to expedite development of oncology drugs and biologics guidance for industry. Published 2018. Accessed July 25, 2020. https://www.fda.gov/media/120721/download

Lesser N, Naaz B. Shifting the drug development paradigm. Deloitte. Published 2018. https://www2.deloitte.com/content/dam/insights/us/articles/4509_Master-protocols/DI_Master-protocols.pdf

Articles

Trials that address multiple questions simultaneously using a master protocol can be operationally complicated. These complexities can be managed, even in studies used to support a marketing application.

How to Address—and Overcome—Operational Challenges in Master Protocol Studies

With recent reports noting that R&D returns in the biopharmaceutical industry have fallen to their lowest levels in nine years,

 life sciences companies need to evaluate the current R&D model and the way clinical trials are designed and implemented. One possible innovation to enhance R&D efficiency is master protocol studies. In FDA draft guidance issued in October 2018, a master protocol is defined as “a protocol designed with multiple sub-studies, which may have different objectives and involves coordinated efforts to evaluate one or more investigational drugs in one or more disease subtypes within the overall trial structure.”

	Common types of master protocol studies include:

		Basket trials, a single investigational drug or a drug combination in multiple disease populations.

		Umbrella trials, which include multiple investigational drugs in a single disease population.

		Other trial designs that may include a combination of design features both of basket and umbrella trials.

	Master protocol studies can provide potential opportunities to shorten R&D timelines, reduce R&D costs, and improve the probability of success-if designed and implemented properly. The uniqueness of the master protocol design is that it starts from a more open beginning and gradually adjusts the design to the direction where there is a higher probability of success. For instance, adding new treatment arms, changing the standard of care arm, adding or removing disease populations, and changing eligibility criteria. These are achieved by utilizing more frequent interim data reviews and decision-making that relies significantly on data currency and data quality. However, the master protocol design has dramatically increased implementation complexities because of the frequent substantial protocol amendments and/or protocol adaptations. As a result, the questions about what, why, when, where, who, and how have become critical to answer.

	Master protocol studies usually are large global studies and involve numerous countries and investigational sites that have different requirements and processes for reviewing protocols. The sites also have different processes and systems in place for patient data, labs, contracts, finance, etc. Besides sponsors and contract research organizations (CROs), many vendors are used in the study for clinical supplies, lab sample processing and analysis, and imaging data review. Sponsors, CROs, and vendors also use many different systems for data capture and analysis. Because of the numerous entities involved, these processes and systems may have significant data overlap and lack the necessary integration.

	A master protocol study can constantly change. It is reflected in the downstream work activities conducted by various parties, including regulatory affairs, ethics committees, institutional review boards (IRBs), sponsors, CROs, vendors, and sites, all of which ultimately impact the patient. In the current R&D model, all of these activities are performed by different companies and organizations using different processes and systems. As a result, interoperability needs to be assessed, with protocol development and any amendments handled by the sponsor or a sponsor-contracted company or consultant.

	To ensure data consistency and an integrated process flow, various process plans, data transfers, and reconciliation agreements are established, which takes significant time and effort to develop and implement at the start-up stage of a trial. In a master protocol study, the development and setup activities need to be conducted again whenever there is a protocol amendment and adaptation that impact the critical process and data identification. That can make it even more challenging than at the initial setup because enrollment is ongoing, and/or a high number of patients are still active in the study.

	Compared to a master protocol study’s innate flexibility and adaptability, a traditional protocol model can seem inflexible, slow, and unclear. In this context, an orchestrated cross-functional, risk-based approach to implement master protocol studies address many of the concerns with a traditional study methodology. The principles established within ICH E6 (R2) provide opportunities to effectively address these challenges, while ensuring human subject protection and reliability of trial data are maintained throughout the life cycle of the clinical trial.

	The implementation of a master protocol study starts with the development of a sound integrated quality and risk management plan (IQRMP) to de-risk the complexity by answering the questions about what, why, when, where, who, and how in relation to an evolving protocol. The IQRMP defines the actions each functional group and party will take to proactively identify, assess, and manage risk throughout the life of the master protocol and each sub-study. As important as predefined actions are to identified risks, an IQRMP also should have the agility and flexibility to adapt to the speed and frequency of the changes with master protocols since it’s impossible to foresee all the risks when the study is initiated. Therefore, rather than trying to predict a fixed future, the IQRMP serves as a tool to understand the data that will be available at each point to make real-time decisions as the study evolves.

	The initial step in the development of an IQRMP is the risk assessment using an instrument such as the risk assessment categorization tool (RACT). The RACT requires the identification of critical process and data identification based upon the protocol and its endpoints and objectives. Those evaluations will evolve as the protocol design advances and connects with functional oversight plans, processes, and systems residing with various parties and stakeholders. This creates an ideal venue to orchestrate the cross-functional and cross-party changes using a risk-based approach. The risk assessment process also ensures that ongoing risk reviews are performed throughout the life cycle of the study.

	These regular reviews offer an opportunity for orchestrated and cross-functional engagement to safeguard important protocol direction decisions with ongoing risk reviews and mitigations. Due to the complexity of master protocol design, it can be valuable to separate out each sub-study from the master protocol while critical processes and data identification are collected as a component of the risk assessment. Once risks are identified for each sub-study, the data is consolidated to identify similarities and prioritize those risks that bring greatest impact to the overall master protocol. Another approach is to “break” the protocol based on what is certain and what is subject to change, then identify the associated critical data and processes according to these “time zones” to help prioritize, while remaining agile and flexible.

	Addressing challenges: Centralized monitoring, RBM

	As previously noted, to achieve the purpose of a master protocol study, data must be entered and cleaned in a timely manner. Data currency and quality directly impact the timeliness and quality of these important study direction decisions as well as the trial’s overall success. However, it’s extremely challenging to maintain high data currency and quality in such fast-paced, complex, large global studies. To help address the related challenges, ICH E6 (R2) allows for varied approaches with a focus on centralized monitoring.

	Centralized monitoring is valuable for master protocol studies due to the speed of study execution, the frequent study adaptations and amendments, and the scope of changes in study implementation. Potential data integrity and subject safety concerns must be identified and investigated promptly. Centralized monitoring, inclusive of advanced data analytics, allows for large volumes of data to be reviewed more quickly than the traditional 100% onsite source data verification (SDV) monitoring approach. Focused, targeted monitoring activities can promptly identify data anomalies for additional root cause analysis and corrective actions by clinical research associates (CRAs).

	A risk-based monitoring (RBM) approach also brings enhanced quality control to master protocols via the use of key risk indicators (KRIs). KRIs are alerts at specific sites, or at the study level, in the form of atypical patterns of data that indicate potential risks related to the conduct of the study to ensure the defined risk-mitigation techniques are effective. Establishing these alerts in a master protocol study provide a just-in-time mechanism to identify the signals and trigger appropriate action plans. Due to the constantly changing nature of master protocol studies, it’s also important to ensure agility and flexibility are built into the KRIs and reviewed at more frequent intervals than traditional protocol designs. These RBM approaches help to align precious time and resources more intelligently in accordance with the evolving protocol design and ongoing risk assessment.

	The protocol’s path: Continuous navigation

	In the evolving journey of the master protocol study, from its initial version to its final iteration, there are many interim timepoints at which data is reviewed and protocol direction decisions are made. An orchestrated risk-based model provides opportunities at these timepoints to establish cross-functional engagement and safeguard these important protocol direction decisions. Its structured framework embedded in the life cycle of the study helps de-risk the inherent protocol complexity and navigate changes. This model provides clarity to the earlier questions about what, why, when, where, who and how, and establishes a continuous model that can be reused as needed in the study duration in its full or partial version.

		“Unlocking R&D Productivity – Measuring the Return from Pharmaceutical Innovation 2018.” Deloitte Center for Health Solutions and GlobalData. 

https://www2.deloitte.com/content/dam/Deloitte/uk/Documents/life-sciences-health-care/deloitte-uk-measuring-return-on-pharma-innovation-report-2018.pdf

		“Master Protocols: Efficient Clinical Trial Design Strategies to Expedite Development of Oncology Drugs and Biologics.” Guidance for industry, FDA. October 2018. 

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/master-protocols-efficient-clinical-trial-design-strategies-expedite-development-oncology-drugs-and

 is Director, Risk-based Monitoring, PPD; 

 is Associate Director, Project Management, PPD

Using a risk-based model to navigate the inherent changes and fluctuations in master protocol studies-and help maintain data integrity throughout.

Rachael Song

Articles

How to Address—and Overcome—Operational Challenges in Master Protocol Studies

De-risking Master Protocol Implementation